Multiple Proteinopathies in Familial ALS Cases With Optineurin Mutations. Issue 2 (20th December 2017)

• Record Type: Journal Article
• Authors: Ayaki, Takashi; Ito, Hidefumi; Komure, Osamu; Kamada, Masaki; Nakamura, Masataka; Wate, Reika; Kusaka, Hirofumi; Yamaguchi, Yuko; Li, Fangzhou; Kawakami, Hideshi; Urushitani, Makoto; Takahashi, Ryosuke
• Is Part Of: Journal of neuropathology and experimental neurology. Volume 77:Issue 2(2018)
• Page Start: 128
• Page End: 138
• Publication Date: 2017-12-20
• Subjects: α-Synuclein -- Amyotrophic lateral sclerosis (ALS) -- Autophagy -- Mitophagy -- Optineurin (OPTN) -- Tau -- TDP-43; Neurology -- Diseases -- Periodicals; Neurology -- Diseases -- Physiopathology -- Periodicals; 616.8047
• DOI: 10.1093/jnen/nlx109
• Languages: English
• ISSNs: 0022-3069

Abstract

Abstract: Optineurin ( OPTN ) is a causative gene in familial amyotrophic lateral sclerosis (ALS) with transactivation response element DNA-binding protein of 43 kDa (TDP-43) protein pathology. Here, we report multiple proteinopathies in familial ALS cases with OPTN mutations. We examined the TDP-43, tau, and α-synuclein pathology of ALS cases with OPTN mutations including 2 previously reported cases (Cases 1 and 2) and 1 newly autopsied case (Case 3) that was clinically diagnosed as ALS and Parkinson disease with a heterozygous E478G OPTN mutation. Pathologic examination of Case 3 showed motor neuron degeneration and depigmentation of the substantia nigra. Neurofibrillary tangles (NFTs) were seen in the hippocampus, pontine tegmentum, and spinal cord. Accumulation of multiple proteins including phosphorylated TDP-43-positive neuronal cytoplasmic inclusions, phosphorylated tau (AT8)-positive NFTs, and α-synuclein-positive Lewy bodies were observed in the substantia nigra. The other 2 cases had a similar distribution of tau pathology, but lacked synuclein pathology. Consecutive sections of Case 3 revealed pTDP-43, AT8, and α-synuclein-positive inclusions in the same neuron and double immunofluorescence staining showed aggregation of different proteins (tau and α-synuclein, or tau and TDP-43) in the same neuron. Our results support the notion that OPTN mutations may lead to multiple proteins aggregation and neuronal degeneration.